Current manufacturing technologies for cell removal from production-scale bioreactors use one of two options: disc stack centrifugation followed by depth filtration, or direct depth filtration (typically used for bioreactor volumes up to 2kL scale with lower cell densities).
Depth filtration approaches have a large footprint, a cumbersome installation process and reach their operational limits with final cell densities of around 50 million cells/mL. Existing technologies will be increasingly challenged due to the further intensification of processes, e.g. by perfusion (concentrated fed-batch systems with cell retention), which will need solutions that can operate with feedstream cell densities over 150 million cells/mL.
This is why BioPhorum has written the Harvest clarification URS. Version 2.0. This outlines biopharmaceutical manufacturers’ requirements for an improved harvest clarification solution that will operate with feedstream cell densities up to 150 million cells/mL in a single-use production scenario.
Finding ultra-high cell density solutions
“Cell removal and clarification is always neglected between upstream and downstream development,” said Hiren Ardeshna, Sr. Scientific Investigator at GlaxoSmithKline. “The recently published Harvest and Clarification URS will enable vendors and development teams to effectively test their technology to handle upstream cell density increases, while enabling intensified downstream processes that meet industry expectations for quality and yield.”
The URS contains requirement details covering functional requirements (e.g. operating temperature and temperature change), qualification requirements (e.g. microbial control), quality requirements (e.g. biocompatibility) and supply chain requirements (e.g. lead times).
To facilitate the development of new technologies, those for the clarification of high cell density feedstreams may be evaluated according to the testing parameters described in the URS’s addendum.
The new URS will bring consistency to the testing performed by vendors and help biomanufacturers to make better decisions about which solution technology they would like to use or investigate further. Without this consistency, there is variability in how vendors can demonstrate what their equipment and solutions can do, which prevents biomanufacturers from properly comparing systems.
The paper supports the original Harvest clarification URS that was written for a harvest clarification solution that will handle ultra-high-density mammalian cell cultures.
Both URSs have been driven by the process technologies chapter of the BioPhorum Biomanufacturing Technology Roadmap. This identified the need for robust harvesting systems that enable cost-effective upstream processing options, e.g. handling high-density suspensions, better/faster equipment cleanability and turnaround.